Lentivirus-based Immunogene Therapy for HIV Infection

基于慢病毒的 HIV 感染免疫基因疗法

• 批准号: 7218687
• 负责人: CARL H. JUNE
• 金额: $ 193.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218687
• 关键词: Lentivirus; based; Immunogene; Therapy; HIV

DESCRIPTION (provided by applicant): The central theme of the proposal is to continue testing lentiviral engineered T cells for safety and efficacy in HIV infection. This proposal continues the progress made recent years by our group in developing immune restoration for HIV using adoptive T cell transfer and the development of lentiviral vectors to engineer intrinsic HIV resistance. We have recently completed the world's first pilot test of lentiviral gene transfer in humans. Results from the first five subjects are encouraging and warrant formal study to optimize the approach under this RFA. This proposal represents a strong and productive interaction between academia and the private sector that is highly motivated in bringing lentiviral vector technology, in general, and T cell gene transfer therapy in particular, to the bedside, and to do this in a safe and rigorous fashion. The overall goal is to carefully establish the safety or our innovative clinical trials by testing laboratory-based hypotheses, while pursuing additional basic investigation of lentiviral engineering for subsequent immunogene transfer trials for HIV/AIDS. The elements of this proposal are as follows:  Clinical Trials Engine: Lentiviral Engineered T Cells for HIV (Project 1, C. June and P. Tebas). This project will test first and second generation lentiviral vectors that express anti-sense HIV for safety and efficacy and trafficking in phase l/ll trials. Effects of lentiviral engineered CD4 T cells on the host virus relationship will be determined using unique patient samples.  Lentiviral Vector Integration in the Clinic (Project 2, F. Bushman): A comprehensive evaluation of lentiviral integration will be done to predict long term safety of lentiviral engineered T cells.  Engineering Innate T Cell Resistance to HIV Infection (Project 3, J. Riley and R. Doms): Improved lentiviral vectors will be developed by targeting TRIMSa and other novel targets using zinc finger nucleases, and a SCID-hu model will be used to select an optimized vector for clinical testing. The program is supported by 3 cores: Core A, the Lentiviral GLP and GMP Vector Core; Core B, the Cell Engineering Core, and Core C, the Administrative and Biostatistics Core. Private sector interactions are established with ViRxSYS Corp. and Sangamo BioSciences, Inc. Together these studies will provide a comprehensive evaluation of the safety and antiviral efficacy of lentiviral vectors for HIIV/AIDS, and they will move the field forward by providing critical safety data for this new and exciting class of vectors. PROJECT 1: Clinical trials engine: lentiviral engineered T cells for HIV (June, C. H.) DESCRIPTION (provided by applicant): The principle that adoptively transferred T lymphocytes have therapeutic promise for HIV infection is well established. Our long range goals are to establish the safety of infusions of lentiviral engineered T cells, and to test second generation transgenes for safety and improved antiviral efficacy. Our long range objective is to obviate the need to take daily antiviral medications in patients with HIV infection. In a recently completed phase I pilot study, we have demonstrated the safety and feasibility of a single infusion of lentiviral engineered autologous CD4 T cells when administered to HIV infected subjects with late-stage, HAART resistant HIV infection. To date, there is no evidence of insert ional mutagenesis, and one subject has experienced a reduction in viral load. The engraftment and persistence of the gene-modified T cells is satisfactory and suggests that the VSV-G pseudotyped HIV-based lentiviral vector system is nonimmunogenic. Based on our previous studies of costimulated CD4 T cells, we now hypothesize that multiple infusions of lentiviral engineered autologous CD4 T cells that express the VRX496 antisense env transgene will lead to a sustained and higher level engraftment. We further hypothesize that the transgene will confer antiviral effects. Two clinical trials are proposed to test these hypotheses. First, we will perform a multiple dose phase l/ll study in patients whose viral replication is suppressed on HAART. Structured treatment interruption will be carried out to assess antiviral efficacy, and lymphoid biopsies will be used to determine tissue trafficking of the engineered CD4 T cells. In trial #2 we will test a lentiviral vector developed in project 3 that expresses a more potent antiviral product. We will compare the relative survival of the T cells transduced with the second generation vector to cells transduced with the original VRX496 vector tested in trial #1. Together, these trials will represent the first formal efficacy tests of lentiviral engineered T cells for their potential to serve as a potent antiviral therapy for treatment of HIV-1 infection. This project interacts with projects 2, and 3, and the project relies on Cores A and B for cGMP lentiviral vector manufacturing and for clinical grade T cell expansion and transduction technology.

描述（由申请人提供）：该提案的中心主题是继续测试慢病毒工程T细胞在HIV感染中的安全性和有效性。该提案延续了我们小组近年来在使用过继性T细胞转移开发HIV免疫恢复和开发慢病毒载体以设计内在HIV抗性方面取得的进展。我们最近完成了世界上第一个在人体内进行慢病毒基因转移的试验。前五个主题的结果令人鼓舞，值得进行正式研究，以优化RFA下的方法。这一提议代表了学术界和私营部门之间强有力和富有成效的互动，这是高度积极性的，将慢病毒载体技术，特别是T细胞基因转移治疗带到床边，并以安全和严格的方式做到这一点。总体目标是通过测试基于实验室的假设来仔细建立我们创新临床试验的安全性，同时为随后的HIV/AIDS免疫基因转移试验进行慢病毒工程的额外基础研究。这项建议的内容如下：  临床试验引擎：用于HIV的慢病毒工程化T细胞（项目1，C。June和P. Tebas）。该项目将在I/II期试验中测试表达反义HIV的第一代和第二代慢病毒载体的安全性和有效性以及运输。将使用独特的患者样本确定慢病毒工程化CD 4 T细胞对宿主病毒关系的影响。  临床中的慢病毒载体整合（项目2，F. Bushman）：将进行慢病毒整合的综合评估，以预测慢病毒工程化T细胞的长期安全性。  工程化先天T细胞对HIV感染的抗性（项目3，J. Riley和R. Doms）：改进的慢病毒载体将通过使用锌指核酸酶靶向TRIMSa和其他新靶点来开发，并且SCID-hu模型将用于选择用于临床测试的优化载体。该项目由3个核心支持：核心A，慢病毒GLP和GMP载体核心;核心B，细胞工程核心;核心C，管理和生物统计学核心。与ViRxplant Corp.和Sangamo BioSciences，Inc.建立了私营部门互动关系。这些研究将为慢病毒载体治疗HIV/AIDS的安全性和抗病毒疗效提供全面的评估，并通过为这类新的令人兴奋的载体提供关键的安全性数据，推动该领域的发展。 项目1：临床试验引擎：用于HIV的慢病毒工程化T细胞（6月，C。H.）的 描述（由申请人提供）：过继转移的T淋巴细胞对HIV感染具有治疗前景的原则已得到充分确立。我们的长期目标是建立慢病毒工程T细胞输注的安全性，并测试第二代转基因的安全性和改善的抗病毒功效。我们的长期目标是使艾滋病毒感染者不需要每天服用抗病毒药物。在最近完成的I期试点研究中，我们已经证明了单次输注慢病毒工程化自体CD 4 T细胞在给予晚期HAART耐药HIV感染的HIV感染受试者时的安全性和可行性。到目前为止，没有插入突变的证据，1例受试者的病毒载量降低。基因修饰的T细胞的植入和持久性是令人满意的，并表明基于VSV-G假型HIV的慢病毒载体系统是非免疫原性的。基于我们先前对共刺激的CD 4 T细胞的研究，我们现在假设多次输注表达VRX 496反义env转基因的慢病毒工程化自体CD 4 T细胞将导致持续和更高水平的植入。我们进一步假设，转基因将赋予抗病毒作用。两个临床试验，提出了测试这些假设。首先，我们将在HAART抑制病毒复制的患者中进行多剂量I/II期研究。将进行结构化治疗中断以评估抗病毒疗效，并将使用淋巴活检来确定工程化CD 4 T细胞的组织运输。在试验#2中，我们将测试项目3中开发的慢病毒载体，该载体表达更有效的抗病毒产物。我们将比较用第二代载体转导的T细胞与用试验#1中测试的原始VRX 496载体转导的细胞的相对存活率。总之，这些试验将代表慢病毒工程化T细胞作为治疗HIV-1感染的有效抗病毒疗法的潜力的第一个正式的疗效测试。该项目与项目2和3相互作用，该项目依赖于核心A和B用于cGMP慢病毒载体生产以及临床级T细胞扩增和转导技术。